Helicobacter pylori is the only bacterium that is a class I carcinogen [1]. I study H. pylori, because of its enormous impact on public health: at least 50% of the world population is persistently infected with this carcinogen. H. py/or/'-related disease includes chronic active gastritis, peptic ulcer disease, MALT lymphoma and gastric adenocarcinoma, the second leading cause of cancer-related deaths in the world. Understanding the mechanisms that H. pylori uses for stomach colonization will lead to new treatment strategies to prevent these diseases. We have found that H. pylori require natural competence, the ability to take up environmental DMA, for stomach colonization. It has been hypothesized that natural competence helps this bacterium adapt to changes in host environment over long periods of time; however our experiments show that natural competence is important at early times during stomach colonization, suggesting it has a second function. This proposal has two Aims: to determine 1) when and 2) how H. pylori natural competence is required during stomach colonization in a mouse model. Completion of these Aims will hone my skills in genetic analysis of H.pylori and manipulation of the mouse model, thus preparing me to begin my own laboratory as an independent scientist. I will work with a mentoring committee to develop three areas: this research to its full potential, my speaking skills in preparation for a search for a faculty position, and my writing skills for future publications and grant applications. In my own laboratory, the long-term goal will be to study mechanisms of natural competence important for stomach colonization and this work will lead to treatment modalities. Targeting the natural competence machinery is an intriguing therapeutic strategy, because it will: i) inhibit colonization, thereby increasing clearance of the bacterium ii) prevent the bacterium from exchanging antibiotic resistance alleles. These studies fulfill the mission of the NIDDK by identifying mechanism for fighting H.pylori infection, the major cause of chronic active gastritis, peptic ulcer disease, MALT lymphoma and gastric adenocarcinoma. Peptic Ulcers are not caused by stress, but rather infection with a bacterium called Helicobacter pylori, which also causes gastric cancer. Studying the bacterium will help us develop new drugs that will rid people of the infection and reduced greatly their risk of developing ulcers or stomach cancer.